Fibrosis In Liver Transplant Recipients Research Articles

Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients

IntroductionVibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent ‘rule-out’ test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to ‘rule-in’ the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients.MethodsAdult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3–4).ResultsAdvanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa.ConclusionThe proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Development of a Radiomics-Based Model to Predict Graft Fibrosis in Liver Transplant Recipients: A Pilot Study.

Liver Transplantation is complicated by recurrent fibrosis in 40% of recipients. We evaluated the ability of clinical and radiomic features to flag patients at risk of developing future graft fibrosis. CT scans of 254 patients at 3-6months post-liver transplant were retrospectively analyzed. Volumetric radiomic features were extracted from the portal phase using an Artificial Intelligence-based tool (PyRadiomics). The primary endpoint was clinically significant (≥F2) graft fibrosis. A 10-fold cross-validated LASSO model using clinical and radiomic features was developed. In total, 75 patients (29.5%) developed ≥F2 fibrosis by a median of 19 (4.3-121.8)months. The maximum liver attenuation at the venous phase (a radiomic feature reflecting venous perfusion), primary etiology, donor/recipient age, recurrence of disease, brain-dead donor, tacrolimus use at 3months, and APRI score at 3months were predictive of ≥F2 fibrosis. The combination of radiomics and the clinical features increased the AUC to 0.811 from 0.793 for the clinical-only model (p = 0.008) and from 0.664 for the radiomics-only model (p < 0.001) to predict future ≥F2 fibrosis. This pilot study exploring the role of radiomics demonstrates that the addition of radiomic features in a clinical model increased the model's performance. Further studies are required to investigate the generalizability of this experimental tool.

Progression of fibrosis in liver transplant recipients with hepatitis C before and after sustained virologic response.

Liver transplant (LT) recipients with untreated hepatitis C (HCV) are at risk for cirrhosis graft failure. The advent of direct acting antiviral agents (DAA) has improved outcomes in HCV. We aim to examine liver transplant outcomes and allograft fibrosis development/progression after sustained virologic response (SVR). We performed a retrospective cohort study of 226 consecutive liver transplant recipients with HCV from 2007 to 2018. The cohort was split into transplants pre (Group A) and post (Group B) 2014 to reflect the introduction of DAAs. Fibrosis was monitored with liver biopsy and non-invasive imaging. Group B had significantly improved HCV treatment rates and earlier SVR compared to Group A, with a cumulative incidence rate of SVR at 2 years of 86.7% versus 15.4% (HR=.11, p<.001). Prior to achieving SVR, Group A demonstrated worsening of fibrosis stage per year (+.21, p<.001) whereas Group B showed minimal change on protocol annual biopsy (-.02, p=.80). After SVR, most patients were followed non-invasively and demonstrated stable or improved fibrosis stage over time. Patients undergoing transient elastography showed regression in fibrosis stage per year (-.19, p<.001). HCV patients undergoing LT after 2014 had higher rates of SVR and improved clinically relevant transplant outcomes, namely less graft loss and death relating to HCV. Fibrosis progression halted or improved after SVR in both cohorts, suggesting that LT recipients with SVR do not require fibrosis monitoring even with established fibrosis prior to SVR.

FRI-494 - Soluble CD163 as a biomarker of liver fibrosis in liver transplant recipients

FRI-494 - Soluble CD163 as a biomarker of liver fibrosis in liver transplant recipients

Quantification of extracellular matrix remodeling for the non-invasive identification of graft fibrosis after liver transplantation

Detecting patients with early post-transplant fibrosis after liver transplantation (LT) is very important. Non-invasive tests are needed to avoid liver biopsies. We aimed to detect fibrosis in liver transplant recipients (LTR) using extracellular matrix (ECM) remodeling biomarkers. ECM biomarkers for type III (PRO-C3), IV (PRO-C4), VI (PRO-C6) and XVIII (PRO-C18L) collagen formation and type IV collagen degradation (C4M) were measured by ELISA in prospectively collected, cryopreserved plasma samples (n = 100) of LTR with paired liver biopsies from a protocol biopsy program. Fibrosis ≥ F2 was present in 29% of patients (median 44 months post-LT). APRI and FIB-4 neither identified significant fibrosis nor were correlated with histopathological fibrosis scores, while ECM biomarkers (AUCs 0.67–0.74) did. The median levels of PRO-C3 (15.7 vs. 11.6 ng/ml; p = 0.002) and C4M (22.9 vs. 11.6 ng/ml; p = 0.006) levels were elevated in T-cell-mediated rejection compared to normal graft function. The median levels of PRO-C4 (178.9 vs. 151.8 ng/ml; p = 0.009) and C4M (18.9 vs. 16.8 ng/ml; p = 0.004) levels were increased if donor-specific antibodies were present. PRO-C6 had the highest sensitivity (100%), NPV (100%) and negative likelihood-ratio (0) for graft fibrosis. To conclude, ECM biomarkers are helpful in identifying patients at risk of relevant graft fibrosis.

Metabolic syndrome, hepatic fibrosis, and steatosis diagnosed by liver stiffness measurement and controlled attenuation parameter after liver transplantation: the impact on long-term survival

ABSTRACT Background Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) are used for diagnosis of liver fibrosis and steatosis. This study aimed to noninvasively evaluate hepatic steatosis and fibrosis in liver transplant recipients using CAP and LSM and the impact on survival of patients. Methods In a prospective study, adult liver transplant recipients were included. CAP and LSM obtained during transient elastography (TE) were used for assessment of hepatic steatosis and fibrosis. Patients were followed during 4 years for mortality as the main outcome after liver transplantation. Results From 296 patients, 24.7% and 25% of liver transplant recipients had liver steatosis and fibrosis in CAP and LSM, respectively. In multivariable Cox regression analysis, etiology of liver disease (NASH versus non-NASH) (HR: 3.125; 95% CI: 1.594–6.134; p = 0.001), and post-transplant diabetes mellitus (PTDM) (HR: 2.617; 95% CI: 1.396–4.926; p = 0.003) were associated with hepatic steatosis after liver transplantation. In multivariable Cox regression analysis, liver fibrosis was an independent predictor of mortality after liver transplantation (HR: 4.926; 95%CI: 1.779–13.513; p = 0.002). Conclusion CAP and LS measurement during TE are useful methods for diagnosis of hepatic steatosis and fibrosis in liver transplant recipients. LS measurement might predict long-term survival of patients.

Noninvasive Diagnostic Methods for the Assessment of Hepatic Fibrosis in Liver Transplant Recipients

Hepatic fibrosis in liver transplant recipients is the main predictive factor for graft function. Diagnostic methods for hepatic fibrosis staging should be available, reproducible, and noninvasive, if possible. We aimed to compare diagnostic methods for the assessment of hepatic fibrosis in transplant recipients: liver biopsy as a reference method, dynamic elastography, and direct and indirect blood markers (the ELF test [Enhanced Liver Fibrosis] test and the FibroTest). We sought to set a cutoff value for each method in order to assess significant liver fibrosis (F ≥2). The study involved 62 patients after liver transplantation. Fibrosis was assessed in biopsy specimens using the METAVIR Score System (F0-F4). To identify clinically significant cutoff values of hepatic fibrosis (F ≥2, F ≥3, F=4) for each method compared, a receiver-operating characteristic (ROC) curve analysis was used. Area under ROC for the prediction of significant fibrosis (F ≥2), advanced fibrosis (F ≥3), and cirrhosis (F=4) for the study group was 0.5938, 0.8952, and 0.9583 for dynamic elastography; 0.7295, 0.7072, and 0.8409 for the ELF test; and 0.4863, 0.8049, and 0.8723 for the FibroTest. The cutoff value for F ≥2 for dynamic elastography was 4.65 kPa; for the ELF test, 9.27; and for the FibroTest, 0.72. The sensitivity and specificity of the tests studied, as compared with biopsy results, increase with increasing severity of hepatic fibrosis. The noninvasive diagnostic methods are of limited value in the diagnosis of early fibrosis stages. In the diagnostic assessment of hepatic fibrosis in its advanced stages, dynamic elastography can be used in conjunction with ELF test as a noninvasive alternative to liver biopsy.

Evaluation of Magnetic Resonance Elastography and Transient Elastography for Liver Fibrosis and Steatosis Assessments in the Liver Transplant Setting.

Liver graft fibrosis affects long-term graft and patient survival in liver transplant recipients. Transient elastography and magnetic resonance elastography are widely used for the assessment of liver fibrosis in routine clinical practice, but are limited in liver transplant settings. The aims of the present study were to evaluate the accuracy of magnetic resonance elastography and transient elastograph in the assessment of liver fibrosis in liver transplant recipients, and to determine the recurrence rates of post-transplant hepatic steatosis and liver fibrosis. A total of 126 consecutive liver transplant recipients were included. Magnetic resonance elastography and transient elastography were performed for to measure liver stiffness. The most common cause of liver transplantation was hepatitis B virus-induced cirrhosis (50%). The mean liver stiffness value with transient elastography was 6.1 ± 3.0 kPa, and the mean magnetic resonance elastography value was 2.7 ± 1.0 kPa. A significant positive correlation was found between magnetic resonance elastography and transient elastography in terms of liver stiffness measurement (r = 0.61, P < .001). Obesity and the underlying etiology of liver diseases did not have any significant negative effect on magnetic resonance elastography and transient elastography measurements. During the follow-up, the post-transplant recurrence rates of hepatic steatosis and hepatic fibrosis were 26% and 37%, respectively. The recurrence rates of post-transplant hepatic steatosis and liver fibrosis were slightly higher in recipients with non-alcoholic fatty liver disease-related cirrhosis than those with viral hepatitisrelated etiologies (44% vs 27%, P = .43; 44% vs 30%, P = .45, respectively). Magnetic resonance elastography and transient elastography are accurate in assessing liver fibrosis in the liver transplant setting. Obesity and the underlying etiology of primary liver disease do not influence the measurements.

Assessment of Steatosis and Fibrosis in Liver Transplant Recipients Using Controlled Attenuation Parameter and Liver Stiffness Measurements.

Aim The primary objective of this study was to evaluate the prevalence of increased controlled attenuation parameter (CAP) and liver stiffness measurements (LSM) as surrogate markers of liver steatosis and fibrosis in liver transplant recipient (LTR). Secondary objectives were to determine the predictors of increased CAP and LSM in population of LTR. Methods In this prospective, cross-sectional study, we have evaluated 175 LTRs' mean age as 61 (53–65) with a functioning graft for more than one year who came for regular outpatient examinations to the Department of Gastroenterology, University Hospital (UH) Merkur, Zagreb, Croatia. Results Of 175 analyzed LTRs, 34.28% had obesity, 64.00% had hypertension, 38.28% had diabetes, and 58.85% had hyperlipidemia. The prevalence of liver steatosis was 68.57%, while the prevalence of severe liver steatosis was 46.85%. On multivariate analysis, independent factors associated with liver steatosis were male gender, total cholesterol as positive predictor, and HDL as negative predictor, and independent factors positively associated with severe liver steatosis were higher body mass index (BMI) and higher triglyceride levels. The prevalence of moderate liver fibrosis was 54.85%, while the prevalence of advanced liver fibrosis was 24%. On multivariate analysis, independent factors positively associated with moderate fibrosis were gamma-glutamyl transferase (GGT) and CAP, while the independent factor positively associated with advanced fibrosis was GGT. Conclusion Our study showed high prevalence of increased CAP and LSM measurements as surrogate markers of liver steatosis and fibrosis. Metabolic syndrome components were highly present and were associated with CAP and LSM values as well as in the pretransplant setting. Due to high prevalence of metabolic comorbidities and nonalcoholic fatty liver disease in LTRs and the lack of the abnormal liver test in a significant number of these patients, TE with CAP may be a reasonable initial assessment for LTRs with one or more components of the metabolic syndrome.

Assessment of Fibrosis in Liver Transplant Recipients: Diagnostic Performance of Shear Wave Elastography (SWE) and Correlation of SWE Findings With Biopsy Results.

OBJECTIVE. Liver transplant patients are monitored for rejection and hepatic fibrosis and often undergo liver biopsies. The purpose of the present study is to determine whether noninvasive shear wave elastography (SWE) can quantify fibrosis in liver transplant recipients, with the aim of decreasing and possibly eliminating unnecessary biopsies for patients with suspected or progressive hepatic fibrosis. MATERIALS AND METHODS. Between May 1, 2015, and December 31, 2017, our prospective study evaluated 111 adult liver transplant patients (age range, 23-79 years) who underwent 147 ultrasound (US) SWE examinations of the right hepatic lobe followed by biopsies. SWE values were compared with the histologic fibrosis (Metavir) scores of the biopsy samples. SWE threshold values were determined using classification and regression tree analysis by anchoring to the degree of fibrosis. The sensitivity, specificity, positive predictive value, and negative predictive value (with 95% CIs) were calculated on the basis of the threshold value. Overall prediction accuracy was estimated using the AUC value from the ROC curve. RESULTS. From the 147 US SWE examinations and liver biopsies, consistent threshold values were identified for patients with no or minimal fibrosis (Metavir scores of F0 and F1, respectively) compared with significant fibrosis (Metavir scores of F2, F3, or F4). A median SWE value of 1.76 m/s or less denoted no or minimal fibrosis, whereas a value greater than 1.76 m/s denoted significant fibrosis. The sensitivity of US SWE examinations in classifying fibrosis was 0.77 (95% CI, 0.5-0.93). The specificity, positive predictive value, and negative predictive value were 0.79 (95% CI, 0.71-0.86), 0.33 (95% CI, 0.19-0.49), and 0.96 (95% CI, 0.91-0.99), respectively. CONCLUSION. Liver transplant patients may avoid liver biopsy if US SWE examination shows a median shear wave velocity of 1.76 or less, which corresponds to a Metavir score of F0 or F1, denoting no or minimal fibrosis.

Shear-wave elastography for the assessment of liver fibrosis in liver transplant recipients treated for hepatitis C virus recurrence.

Direct-acting antiviral agents have revolutionized hepatitis C therapy, and are also found to be effective in the liver transplant setting. The extent of liver fibrosis influences patient management and is used to monitor therapeutic effects. Shear-wave elastography (SWE) is a relatively new imaging-based method that has not yet been studied extensively in liver transplant patients. Our aim was to study the effect of direct-acting antivirals in heaptitis C recurrence on liver stiffness determined by SWE. A total of 23 liver transplant patients with hepatitis C recurrence were enrolled in this prospective study. The patients underwent 24 weeks of ombitasvir/paritaprevir/ritonavir+dasabuvir±ribavirin combination therapy. Elastographic examinations, serological tests and laboratory tests were performed, and serum biomarkers of liver fibrosis were calculated the day before treatment (baseline) and at the end of the treatment. All our patients became hepatitis C virus RNA negative by the end of the treatment. Median liver stiffness values decreased significantly after treatment compared with baseline (8.72±3.77 vs. 7.19±2.4 kPa; P<0.001). Among the studied laboratory values, a significant decrease was observed in the levels of alanine aminotransferase, aspartate aminotransferase and γ-glutamyltransferase, whereas international normalized ratio levels increased. Serum biomarkers, namely aspartate aminotransferase-to-platelet ratio index and Fibrosis-4, decreased significantly after treatment compared with baseline. In the present study, SWE was succesfully used to monitor the beneficial therapeutic effects of direct-acting antivirals in hepatitis C recurrence following liver transplantation. We believe that SWE is a useful noninvasive diagnostic tool in the follow-up of hepatitis C treatment in liver transplant patients.

Routine Laboratory Blood Tests May Diagnose Significant Fibrosis in Liver Transplant Recipients with Chronic Hepatitis C: A 10 Year Experience.

Background and Aims: The aims of our study were to determine whether routine blood tests, the aspartate aminotransferase (AST) to Platelet Ratio Index (APRI) and Fibrosis 4 (Fib-4) scores, were associated with advanced fibrosis and to create a novel model in liver transplant recipients with chronic hepatitis C virus (HCV). Methods: We performed a cross sectional study of patients at The University of California at Los Angeles (UCLA) Medical Center who underwent liver transplantation for HCV. We used linear mixed effects models to analyze association between fibrosis severity and individual biochemical markers and mixed effects logistic regression to construct diagnostic models for advanced fibrosis (METAVIR F3-4). Cross-validation was used to estimate a receiving operator characteristic (ROC) curve for the prediction models and to estimate the area under the curve (AUC). Results: The mean (± standard deviation [SD]) age of our cohort was 55 (±7.7) years, and almost three quarter were male. The mean (±SD) time from transplant to liver biopsy was 19.9 (±17.1) months. The mean (±SD) APRI and Fib-4 scores were 3 (±12) and 7 (±14), respectively. Increased fibrosis was associated with lower platelet count and alanine aminotransferase (ALT) values and higher total bilirubin and Fib-4 scores. We developed a model that takes into account age, gender, platelet count, ALT, and total bilirubin, and this model outperformed APRI and Fib-4 with an AUC of 0.68 (p < 0.001). Conclusions: Our novel prediction model diagnosed the presence of advanced fibrosis more reliably than APRI and Fib-4 scores. This noninvasive calculation may be used clinically to identify liver transplant recipients with HCV with significant liver damage.

Impact of Everolimus-Based Immunosuppression on Efficacy, Safety and Progression of Fibrosis in Hepatitis C Virus Positive De Novo Liver Transplant Recipients: 12 Months Results from H2304 Study

Introduction: Progression of fibrosis in liver transplant recipients (LTxR) with recurrent hepatitis C virus (HCV) infection has been identified as a crucial factor influencing graft and patient survival. Everolimus (EVR) is associated with antifibrotic and antiproliferative effects in several animal models of liver fibrosis. Present study evaluated the effect of EVR on HCV-associated fibrosis progression in de novo LTxR. Methods: H2304 (NCT00622869) is a 24-month (M), multicenter, open-label study. A total of 719 de novo LTxR were randomized 1:1:1 after 30 days of run-in period with tacrolimus (TAC) ± mycophenolic acid to receive either EVR (C0 3-8ng/mL)+reduced TAC (C0 3-5ng/mL; EVR+rTAC, N=245) or EVR (C0 6-10ng/mL)+TAC withdrawal (TAC-WD; N=231) at M4 or standard TAC (C0 6-10ng/mL; TAC-C, N=243); all with steroids. Composite efficacy failure (treated BPAR, graft loss, death) and renal function (RF) were assessed at M12 in the overall study group. In the HCV+ population, fibrosis progression was evaluated using the Ishak system and change of HCV viral load from baseline [BL] to M12 was determined. Comparison of EVR+rTAC vs TAC-C is presented as enrollment into TAC-WD arm was stopped early due to a high acute rejection rate. Results: In the overall study population, composite efficacy failure was comparable in both treatment groups (6.7% EVR+rTAC vs 9.7% TAC-C; p=0.23); similar pattern was observed in the HCV subgroup (Table). Overall population showed significantly lower rate of tBPAR with EVR+rTAC vs TAC-C (2.9% vs 7.0%; p=0.03), while tBPARs were more frequent with EVR+rTAC in HCV+ patients (3.8% vs 1.3%). The EVR+rTAC group had superior RF over TAC-C (80.9 vs 70.3 mL/min/1.73 m2, p< 0.001) at M12, with similar results in HCV+ patients. Fibrosis progression ≥1 stage from BL to M12 was lower in EVR+rTAC group; however the number of biopsies was limited. Change in fibrosis from BL to M12 was comparable in both treatment groups. At BL, the mean viral load was higher for EVR+ rTAC to TAC-C (6.4 vs 5.9); the difference was maintained up to M12 (6.6 vs 6.1). Study drug discontinuations in HCV+ patients were comparable between the groups (EVR+rTAC 23.4% vs TAC-C 20.0%) and there were no differences in anti-HCV treatment use post-LTx. Safety profile in HCV+ patients was comparable to the overall study population.[Table: Month 12 data in HCV+ patients]Conclusions: This study showed comparable efficacy and superior RF with early EVR-facilitated TAC reduction compared to TAC-C in HCV+ patients reflecting the overall H2304 study results. EVR + rTAC treatment demonstrated similar patterns of HCV replication with numerically less fibrosis progression compared to TAC-C. Impact of EVR+ rTAC on fibrosis progression needs confirmation by M24 biopsy results.

Effects of ethnicity and socioeconomic status on survival and severity of fibrosis in liver transplant recipients with hepatitis C virus

The ethnicity and socioeconomic status of the host may affect the progression of hepatitis C virus (HCV). We aimed to compare survival and fibrosis progression in Hispanic white (HW) and non-Hispanic white (NHW) recipients of liver transplantation (LT) with HCV. All HW and NHW patients with HCV who underwent transplantation between January 2000 and December 2007 at 2 centers were retrospectively assessed. The primary outcomes were the time to death, death or graft loss due to HCV, and significant fibrosis [at least stage 2 of 4]. Five hundred eleven patients were studied (159 HW patients and 352 NHW patients), and the baseline demographics were similar for the 2 groups. NHW patients were more likely to be male, to have attended college, and to have private insurance, and they had a higher median household income (MHI). The unadjusted rates of survival (log-rank P = 0.93), death or graft loss due to HCV (P = 0.89), and significant fibrosis (P = 0.95) were similar between groups. In a multivariate analysis controlling for center, age [hazard ratio (HR) per 10 years = 1.43, P = 0.01], donor age (HR per 10 years = 1.25, P < 0.001), and rejection (HR = 1.47, P = 0.048) predicted death, whereas HW ethnicity (HR = 1.06, P = 0.77) was not significant. Independent predictors of significant fibrosis were HW ethnicity (HR = 2.42, P = 0.046), MHI (HR per $10,000 = 1.11, P = 0.01), donor age (HR per 10 years = 1.13, P = 0.02), cold ischemia time (HR = 1.06, P = 0.03), and the interaction between ethnicity and MHI (HR = 0.82, P = 0.03). In conclusion, there is no difference in post-LT survival or graft loss due to HCV between HW patients and NHW patients. Socioeconomic factors may influence disease severity; this is suggested by our findings of more significant fibrosis in HW patients with a low MHI.

Limiting Hepatitis C Virus Progression in Liver Transplant Recipients Using Sirolimus-Based Immunosuppression

Hepatitis C virus (HCV) causes progressive liver fibrosis in liver transplant recipients and is the principal cause of long-term allograft failure. The antifibrotic effects of sirolimus are seen in animal models but have not been described in liver transplant recipients. We reviewed 1274 liver recipients from 2002 to 2010 and identified a cohort of HCV recipients exposed to sirolimus as primary immunosuppression (SRL Cohort) and an HCV Control Group of recipients who had never received sirolimus. Yearly protocol biopsies were done recording fibrosis stage (METAVIR score) with biopsy compliance of >80% at both year one and two. In an intent-to-treat analysis, the SRL Cohort had significantly less advanced fibrosis (stage ≥2) compared to the HCV Control Group at year one (15.3% vs. 36.2%, p < 0.0001) and year two (30.1% vs. 50.5%, p = 0.001). Because sirolimus is sometimes discontinued for side effects, the SRL Cohort was subgroup stratified for sirolimus duration, showing progressively less fibrosis with longer sirolimus duration. Multivariate analysis demonstrated sirolimus as an independent predictor of minimal fibrosis at year one, and year two. This is the first study among liver transplant recipients with recurrent HCV to describe the positive impact of sirolimus in respect of reduced fibrosis extent and rate of progression.

Chronic Allograft Hepatitis C Infection in Liver Transplant Recipients: Fibrosis Progression in Sustained Virological Response and In Situ Hybridization Negative Allografts

Purpose: Allograft hepatitis C (HCV) infection is a major problem among liver transplant (LT) recipients with chronic HCV with an accelerated course post-transplantation. Cirrhosis occurs in 6-30% within 5 years. Therapy is usually offered when liver biopsy demonstrates Ishak fibrosis >1 with ongoing necro-inflammatory activity, and stopped per individual institution protocols after confirming sustained virological response (SVR). The major objective of treatment of recurrent chronic hepatitis C after OLT is to prevent progression to cirrhosis and thereby prevent loss of the graft. The aim of our study is to examine the progression or regression of HCV related fibrosis in LT recipients with SVR. Methods: This is a retrospective chart review of the LT recipients treated for HCV allograft infection. LT recipients who had a substantial follow up after SVR and had corresponding liver biopsies at least annually, and without coexisting conditions that may cause fibrosis were only included in the study. We utilized Ishak scoring system for grading and staging, and to avoid operator variability only one liver pathologist scored all of the biopsies. Results: A total of 16 LT recipients matching the criteria were identified. Details are in the enclosed table. Clinically significant HCV activity in the allografts warranting treatment was noted at a median of 129 days from the time of LT. Histologically this corresponded to HCV hepatitis activity Ishak 6 and fibrosis Ishak 1 (medians). Interferon based regimens were utilized in conjunction with ribavirin, and in varying doses subject to recipient's tolerance. Allograft biopsies and HCV serologies were followed for a median of 880 days from the serological HCV clearance. At the last histological follow up, with SVR, 2 was the median Ishak fibrosis score. 37.5% of the allografts demonstrated an increase in Ishak fibrosis score by 2 median points (1-3) while 25% demonstrated an improvement by 1 point. The remaining 37.5 % demonstrated no change in fibrosis score. Conclusion: In our study cohort, in spite of HCV-RNA absence in serum and the allograft, fibrosis progressed to some degree in 37.5% of the allografts. Possible mechanisms to explain this phenomenon are persistent, low grade, graft cellular immune response to HCV, which may take years to disappear or the currently available tests are not sufficiently sensitive to detect low level HCV RNA leading to a low level persistent replication state in the graft or other yet unknown mechanisms. It remains to be verified if continuation of treatment beyond SVR for a certain period of time, which also needs to be defined, will result in better outcome.Table

Maintenance ribavirin monotherapy delays fibrosis progression in liver transplant recipients with recurrent hepatitis C at high risk of progression

Fibrosis in liver transplant recipients with recurrent HCV is fast, yet, different patterns of progression are recognized. To investigate histological findings associated with maintenance ribavirin monotherapy in patients with recurrent HCV transplanted > or =4 years earlier. 14 recipients at high risk of progression (fibrosis progression rate >0.33 units/year and/or persistently elevated ALT) were assigned to receive ribavirin for 3 years. 11 patients at lower risk of progression (FPR < or =0.33 units/year and normal ALT) as controls. Biopsies were obtained yearly since transplant and 7 consecutive biopsies were evaluated. Improved necroinflammation (reduction > or =2 grading) was observed in 7 treated with ribavirin and 3 untreated patients, while 1 and 3 patients worsened respectively. Fibrosis improved (reduction >1 staging) in 2 ribavirin-treated patients, unchanged in 10 and worsened (increase > or =1 staging) in 2. Fibrosis progression decreased from 0.48+/-0.27 observed during the 3-year pre-treatment period to 0.04+/-0.31 units/year (p=0.003) during the 3 years of ribavirin. Among untreated fibrosis remained unchanged in 1 and worsened in 10 (p<0.001), yearly fibrosis progression rate increasing from 0.15+/-0.17 units/year to 0.42+/-0.39 units/year (p=0.10). Maintenance ribavirin monotherapy delays fibrosis progression in high risk patients, offering an alternative strategy for those failing to respond to conventional treatment.

Gene Expression Patterns That Correlate With Hepatitis C and Early Progression to Fibrosis in Liver Transplant Recipients

Liver transplant recipients infected with hepatitis C virus (HCV) develop recurrent hepatitis soon after transplantation and, in some cases, progress to fibrosis within the first 2 years. Our goals were to identify molecular processes influencing the liver disease progression and to find potential gene markers of early fibrosis. We performed gene expression profiling on serial liver biopsy specimens obtained from 13 (11 infected and 2 uninfected) transplant recipients within the first year after transplantation at 0, 3, 6, and 12 months. The data were compared with clinical observations and with a gene expression database obtained for 55 nontransplant HCV-infected and uninfected liver samples. We identified several specific gene expression patterns. The first pattern was unique for the transplant recipients regardless of their infection status. The corresponding genes encoded stress response proteins and blood proteins involved in coagulation that were differentially expressed in response to posttransplantation graft recovery. The second pattern was specific to HCV-infected samples and included up-regulation of genes encoding components of the interferon-mediated antiviral response and immune system (antigen presentation, cytotoxic response). This up-regulation pattern was absent or suppressed in the patients who developed early fibrosis, indicating that the disease progression might result from an impaired liver response to infection. Finally, we identified gene expression patterns that were specific for 12-month biopsy specimens in all 4 HCV-infected patients who developed early fibrosis. The identified gene expression patterns may prove useful for diagnostic and prognostic applications in HCV-infected patients, including predicting early progression to fibrosis.

774 Interferon-based treatment for recurrent HCV infection does not influence the progression of hepatic fibrosis in liver transplant recipients

774 Interferon-based treatment for recurrent HCV infection does not influence the progression of hepatic fibrosis in liver transplant recipients